PROJECT ABSTRACT Diabetes mellitus (DM) impacts millions of people worldwide, creating a significant burden on healthcare costs and decreasing quality of life for those affected. The pathological processes due to DM manifest severely in the nervous system. DM-induced nerve damage often presents as diabetic peripheral neuropathy (DPN), where sensory nerve loss leads to concurrent pain and numbness, particularly in the limbs. DPN also manifests itself in the cornea, where a high density of sensory nerves makes it particularly susceptible to the effects of hyperglycemia, resulting in a complication termed diabetic neurotrophic keratopathy (DNK). The loss of sensation and neurotrophic nourishments makes patient susceptible to injuries, increasing the likelihood of persistent or unhealable wound, ulceration, infection and possibly blindness. Moreover, the ability of the injured corneal sensory nerve to regenerate is impaired in the diabetic patients. Knowledge of the processes that guide nerve regeneration and pathological mechanisms of DM in delaying this process are still largely unknown. The goal of this proposal is to identify the roles of the class 3 semaphorins in mediating the regeneration of the corneal sensory nerves, and whether their expression and function are altered in diabetes. The semaphorins are a family of proteins most well-known for their ability to act as directional cues to growing axons in the embryo. Our recent data suggests that expression of Sema3C is up-regulated in the corneal epithelium after wounding and this up-regulation is suppressed in diabetic cornea. The central hypothesis of this proposal is that expression of the Sema3s and their receptors are altered after corneal wounding in a manner conducive to increased axon regeneration, and that this healing response is perturbed by DM. This proposal will first examine time-dependent expression changes of these molecules in both epithelium and trigeminal/sensory nerves after wounding in normal and diabetic mouse corneas. The functions of the various Sema3s and therapeutic potential of Sema3C in sensory nerve regeneration, particularly in diabetic corneas, will then be assessed both in vitro and in vivo. The results from this proposal should increase our understanding of DNK at the molecular and cellular levels, and may lead to the development of therapies that treat DPN, where there is great unmet clinical need. Completion of the proposed study will provide the trainee with additional independence in how to ask a scientific question, design a study, discuss the results with others, and use data to generate future questions; these are skills important to both basic science research as well as clinical medicine, and will ensure a successful and productive career as a physician-scientist.